This is a competitive renewal application for an ongoing project aimed at testing the hypothesis that an autoimmune process directed against brain antigens is involved in the etiology or pathogenesis of psychotic symptoms in a subgroup of schizophrenics patients. During the 2 years so far funded, 118 schizophrenic patients and 96 controls have been studied cross-sectionally. Preliminary data show that 31% schizophrenics fall into an immunologically abnormal subgroup who can be immunologically distinguished from normal controls and immunologically normal schizophrenics. Extensive developmental work has also been carried out on the detection of circulating specific antibrain immunoglobulin and anti-brain cell-mediated immunologic responses. Preliminary results using these methods suggest that there is an increased mitotic stimulation of lymphocytes by brain antigens and specific immunoglobulins binding to these antigens in some schizophrenics. During the period of this renewal, recruitment of the cross-sectional portion of the study will be completed to include 180 schizophrenics (including 60 never-medicated patients) and 30 non-psychotic, brain damaged individuals. A longitudinal study of 40 immunologically abnormal and 40 immunologically normal schizophrenic patients will also begin. Each patient will be followed for one year with weekly ratings of clinical state and monthly immunologic assessments. During exacerbations of psychotic symptoms, immunologic tests will be done weekly. If autoimmune mechanisms play a role in the pathogenesis of psychotic symptoms in the immunologically abnormal patients, then clinical and immunologic state measures will be predicted to covary over time only in that subgroup. Furthermore, in the immunologically abnormal subgroup, changes in some immunologic measures may temporally precede the worsening of psychotic symptoms. This is the first multidimensional investigation of the autoimmune hypothesis in schizophrenia and the first attempt to study immunologic phenomena in schizophrenic patients longitudinally.